Project Summary There is a critical need for improved contraceptive methods in the U.S. and worldwide. Nearly half of all pregnancies in the U.S. are unintended. Not surprisingly, the majority of unintended pregnancies occur in women who are non-users of contraception. Although there are diverse reasons for non-use, many women have a strong aversion to using exogenous hormones, due to both real and perceived side effects. We believe that contraceptive satisfaction and use would be substantially increased by the availability of a non-hormonal, user-controlled contraceptive method that does not require coitally-timed actions, nor daily intervention. We believe we can create such a non-hormonal contraceptive method by directly delivering to the vagina (via intravaginal ring (IVR)) sperm-binding antibody (Ab) that agglutinates and traps sperm in mucus, thereby preventing sperm from swimming through mucus and reaching the egg. Although validated in animal models in the 1980s and 1990s, the concept of using Ab as a contraceptive was not yet practical due to high costs of Ab production, formulation hurdles associated with passive immunization, as well as the variability in the intensity, and uncertain reversibility, of Ab response induced by active contraceptive vaccines. Given the remarkable advances in bioprocessing that have greatly reduced the costs of Ab manufacturing, we believe the time is now ripe to develop a non-hormonal contraceptive based on sustained passive immunization of the vagina with Ab. Our approach is based on a well characterized and validated antigen target present on human sperm, and we have a fully human monoclonal Ab that binds this antigen in all 100 semen samples tested; we term this IgG mAb human contraceptive antibody (HCA). We have further enhanced the sperm-agglutination potency of HCA by engineering a novel multimeric construct comprised of a total of six Fab domains (i.e. 4 additional Fabs linked to the parent IgG molecule). We term this construct MM006. By incorporating multiple Fab domains while preserving Fc, we substantially improved its agglutination speed and potency while retaining the stability as well as ease of commercial manufacturing and purification of the parent IgG. Our goal in this SBIR is to validate the efficacy of MM006 in vivo. Since MM006, like its parent HCA, only binds to human sperm, this precludes direct evaluation of contraceptive efficacy in animals. Instead, in this Phase I SBIR application, we will scale up the production of MM006, our multimeric HCA construct (Aim 1), and assess potential contraceptive efficacy by evaluating progressive motility of human sperm in the sheep vagina (Aim 2), which is anatomically similar to that of humans. MM006 will be vaginally delivered, followed by human semen and brief episode of simulated intercourse. Sperm motility in the vaginal secretions will then be assesed. If successful, our proposed work will strongly support development of an IVR that could provide sustained release of MM006 in a Phase II SBIR proposal. Such a non-hormonal contraceptive IVR could address a major unmet need in the marketplace.